Taste is a fundamental sense, which increasingly has been implicated in dietary choices that contribute to obesity and thus to human health. The sense of taste is mediated by taste buds comprising aggregates of heterogeneous receptor cells within specialized papillae on the tongue. In adult mammals, taste receptor cells, despite their functional similarities to neurons, are continually renewed throughout life, like epithelial cells.It is likely due to this continual turnover, however, that the taste system is exceptionally prone to disruption by agents that affect cell proliferation. In particular, head and neck cancer patients receiving radiotherapy virtually always experience loss or distortion of their sense of taste that can persist for years. Numerous chemotherapies also interrupt taste function, again presumably because of the regenerative nature of taste buds. To ascertain how these treatments cause taste dysfunction, it is important to have a clear understanding of the fundamental mechanisms of taste bud cell renewal. The current model of taste bud regeneration has been adopted primarily from studies of epidermis: presumed taste bud stem cells self-renew and generate transit amplifying cells, which together comprise the proliferating taste progenitor population tha gives rise to post-mitotic taste precursor cells which in turn differentiate into mature taste receptor cells. The model is limited in detail and only partially supported by current data, but nonetheless provides an excellent framework for our efforts to define the taste progenitor pool, and elucidate how it continually produces the correct complement of ~3 differentiated taste cell types. While we have some understanding of the cellular underpinnings of taste cell renewal, molecular regulation of this process is largely unexplored. Using conditional molecular genetics in mice, we have shown that the Wnt/-catenin pathway, a key regulator of development and homeostasis in multiple tissues is required for taste bud formation in embryos. Our new data suggest that this pathway also regulates adult taste cell renewal. Thus, in the following 2 specific aims, we will used conditional, tissue specific molecular genetic tools to test the hypothesis that: Taste buds continually renew from a specialized set of progenitor cells via processes that are distinct from the surrounding epithelium, and regulated by Wnt/-catenin signaling. Aim 1. Define the cell lineage and kinetics of taste receptor cell renewal in adult mice Aim 2. Define Wnt/-catenin function in discrete stages of taste cell renewal. In elucidating these mechanisms, we will gain crucial insight into cellular and molecular mechanisms of taste bud regeneration. In the long term, we will leverage these advances to explore how this process is disrupted in patients receiving conventional cancer therapies.